This year, we will newly diagnose one million Americans with heart failure at a cost of 30 billion dollars. Yet, only two thousand Americans will receive heart transplants and far fewer will receive mechanical ventricular assist devices. Emerging technologies include gene therapy which has the potential to save millions of lives. During the prior funding period we further developed an exciting new cardiac surgical technique, molecular cardiac surgery with recirculating delivery (MCARD), arguably the most efficient delivery system in the world for therapeutic genes in adult large animal myocardium. MCARD uses cardiopulmonary bypass with surgical isolation of the heart in vivo with delivery in situ. Use of MCARD to deliver AAV1 expressing SERCA2a results in efficient global LV transduction and significant improvement in EF, downregulation of TGF, inhibition of fibrosis and apoptosis as well as reversal of maladaptive remodeling. These promising preclinical results lead directly to the review by the FDA of a Pre-IND package, Molecular Cardiac Surgery Mediated Administration of AAV Encoding Sarcoplasmic Reticulum ATPase Gene in Patients with Heart Failure on 7-15-2014 in preparation for a First-In Man, First-In World clinical trial of gene therapy in patients with heart failure using cardiopulmonary bypass for vector delivery. We plan to build on these exciting results in the current proposal with three specific aims for molecular regenerative therapy in patients with ischemic cardiomyopathy - the cause of heart failure in 70% of Americans with this disease: 1) Delivery of AAV encoding miR-590 to induce proliferation of otherwise senescent adult cardiac myocytes; 2) Delivery of AAV encoding membrane bound stem cell factor (mSCF) to recruit and activate c-kit positive cardiac progenitor cells in the myocardium and 3) Development of a novel single-vector rapamycin-inducible promoter system to allow for long-term control of the expression of mSCF and miR-590 to optimize safety and efficacy and to allow for preemptive gene therapy in the setting of a future MI. This highly innovative proposal may change the paradigm of cardiac surgery from a palliative-only therapy to a molecular regenerative and preemptive cytoprotective intervention for selected patients.